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Tetrodotoxin-sensitive voltage-gated sodium channels regulate bladder afferent responses to distension

Grundy, Lukea,b,*; Erickson, Andelaina,b; Caldwell, Ashleea,b; Garcia-Caraballo, Soniaa,b; Rychkov, Grigorib; Harrington, Andreaa,b; Brierley, Stuart M.a,b

doi: 10.1097/j.pain.0000000000001368
Research Paper

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a prevalent, chronic bladder disorder that negatively impacts the quality of life for ∼5% of the western population. Hypersensitivity of mechanosensory afferents embedded within the bladder wall is considered a key component in mediating IC/BPS symptoms. Bladder infusion of voltage-gated sodium (Nav) channel blockers show clinical efficacy in treating IC/BPS symptoms; however, the current repertoire of Nav channels expressed by and contributing to bladder afferent function is unknown. We used single-cell reverse-transcription polymerase chain reaction of retrogradely traced bladder-innervating dorsal root ganglia (DRG) neurons to determine the expression profile of Nav channels, and patch-clamp recordings to characterise the contribution of tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) Nav channels to total sodium current and neuronal excitability. We determined the TTX-S and TTX-R contribution to mechanosensitive bladder afferent responses ex vivo and spinal dorsal horn activation in vivo. Single-cell reverse-transcription polymerase chain reaction of bladder-innervating DRG neurons revealed significant heterogeneity in Nav channel coexpression patterns. However, TTX-S Nav channels contribute the vast majority of the total sodium current density and regulate the neuronal excitability of bladder DRG neurons. Furthermore, TTX-S Nav channels mediate almost all bladder afferent responses to distension. In vivo intrabladder infusion of TTX significantly reduces activation of dorsal horn neurons within the spinal cord to bladder distension. These data provide the first comprehensive analysis of Nav channel expression within sensory afferents innervating the bladder. They also demonstrate an essential role for TTX-S Nav channel regulation of bladder-innervating DRG neuroexcitability, bladder afferent responses to distension, and nociceptive signalling to the spinal cord.

TTX-S Nav channels expressed in bladder-innervating dorsal root ganglia regulate neuroexcitability, bladder afferent responses to distension ex vivo, and nociceptive bladder afferent signalling to the spinal cord in vivo.

aVisceral Pain Research Group, Centre for Neuroscience, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia

bCentre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia

Corresponding author. Address: Visceral Pain Research Group, Flinders University, Level 7, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia 5000, Australia. Tel.: +61 8 8128 4858. E-mail address: luke.grundy@flinders.edu.au (L. Grundy).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painjournalonline.com).

Received June 14, 2018

Received in revised form July 17, 2018

Accepted August 02, 2018

© 2018 International Association for the Study of Pain
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